Cell death and longevity: implications of Fas-mediated apoptosis in T-cell senescence.
Two prominent features of immune senescence are altered T-cell phenotype and reduced T-cell response. We have previously shown that T-cell senescence is greatly reduced in CD2-fas transgenic mice, in which the Fas apoptosis molecule is constantly expressed on T cells. Using a different experimental approach, the relationship between T-cell senescence and apoptosis was analyzed on human peripheral blood mononuclear cells. The results indicate that there was increased apoptosis of CD45RO- (CD45RA+) T cells upon activation. We propose that this could account for the increase in CD45RO+ "memory" T cells with aging in humans. T-cell responsiveness remained high in CD2-fas transgenic aged mice, but there was no increase in overall life span of these mice. Increased T-cell responsiveness was associated with an increased acute-phase response and serum amyloid A deposition in the glomerulus of aged CD2-fas transgenic mice. Therefore, restoration of the T-cell immune function using a CD2-fas transgene produced undesirable side-effects to aged transgenic mice. In addition to its role in activation-induced cell death, Fas-mediated apoptosis may be important in deleting T cells in response to DNA damage. It may also inhibit cell-cycle progression by cleaving various kinases and DNA repair enzymes. We observed that cell lines derived from human premature aging diseases have a higher sensitivity to Fas-mediated apoptosis. The implications of these observations are discussed.
Mountz
J D
JD
Department of Medicine, University of Alabama at Birmingham 35294-0007, USA. John.Mountz@ccc.uab.edu
Wu
J
J
Zhou
T
T
Hsu
H C
HC
D000210:Acute-Phase Reaction / Q000276:immunology; D000686:Amyloidosis / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D018801:CD2 Antigens / Q000235:genetics / Q000276:immunology; D016922:Cellular Senescence / Q000276:immunology; D004249:DNA Damage; D005544:Forecasting; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
D018801:CD2 Antigens; D019014:fas Receptor